PB2099: A FIRST-IN-HUMAN PHASE 1 TRIAL OF NX-1607, A FIRST-IN-CLASS ORAL CBL-B INHIBITOR, IN PATIENTS WITH ADVANCED MALIGNANCIES INCLUDING RICHTER TRANSFORMATION DLBCL
Authors: A. Sharp, A. Williams, S. Blagden, R. Plummer, D. Hochhauser, M. G. Krebs, S. Pacey, J. Evans, S. Whelan, S. Nandakumar, S. Rogers, K. L. Jameson, F. G. Basile, J. de Bono, H.-T. Arkenau
Journal: HemaSphere (2022)

Background: Standard of care treatment for diffuse large B-cell lymphoma type Richter transformation (DLBCL-RT) is combination chemo-immunotherapy but is limited by poor response rates and lack of durability. Recent studies have shown some clinical benefit with PD-1 blockade treatment in DLBCL-RT including deep responses, highlighting that T-cell targeted immunotherapy may improve outcomes. Casitas B-lineage lymphoma proto-oncogene B (CBL-B) is an E3 ubiquitin ligase expressed in multiple immune cell lineages, which in contrast to cell surface immune checkpoints, acts as a regulator of both T and NK cell activation. Inhibition of CBL-B enhances T-cell response to suboptimal priming and restores response in exhausted T cells. In addition, NK cells deficient in CBL-B have increased cytokine production upon activation. Thus, CBL-B is a promising immune-oncology target and may overcome challenges seen with other T-cell directed therapies. NX-1607 is an oral small molecule inhibitor of CBL-B that has demonstrated anti-lymphoma activity in murine models as both a single agent, and in combination with anti-CD19 monoclonal antibodies. In addition to increased anti-tumor T-cell activity, NX-1607 also potentiates the anti-tumor cytotoxic and antibody-dependent cellular cytotoxicity (ADCC) activity of NK cells. Therefore, NX-1607 may be effective as a single agent or it may significantly enhance efficacy of other anti-tumor agents in a subset of hematologic malignancies. Aims: The main objective is to establish the safety and tolerability, characterize the pharmacokinetics (PK) and pharmacodynamics (PD), and determine the early clinical activity of NX-1607 in advanced solid malignancies including DLBCL-RT. Methods: NX-1607-101 is a first-in-human, multicenter, open-label, Phase 1 dose escalation and expansion trial evaluating NX-1607 in a variety of indications including DLBCL-RT. It will be conducted at approximately 20 sites in the UK and US. NX-1607 will be given orally once daily at doses ranging from 5 to 100 mg in up to 6 dose levels. After determining the expansion dose, up to 8 cohorts in Phase 1b will be investigated in patients with subsets of advanced cancers including DLBCL-RT (n = 16). Key eligibility criteria include patients with metastatic or unresectable disease that have progressed after prior therapy and for whom standard therapy with proven clinical benefit does not exist, is no longer effective, or is not appropriate. Prior treatment with CAR-T cells with washout is allowed, but a history of active autoimmune disease is not. The primary endpoints are safety and maximum tolerated dose (Phase 1a) and objective response rate (Phase 1b) of NX-1607. Secondary endpoints (Phase 1a and Phase 1b, unless otherwise indicated) include PK/PD, objective response rate (Phase 1a), duration of response, disease control rate, progression-free survival, overall survival, and safety (Phase 1b). Results: Dose escalation is ongoing. Summary/Conclusion: Accrual is ongoing. Clinical trial information: NCT05107674.